Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS

Simona Rossi, Alessia Serrano, Valeria Gerbino, Alessandra Giorgi, Laura Di Francesco, Monica Nencini, Francesca Bozzo, Maria Eugenia Schininà, Claudia Bagni, Gianluca Cestra, Maria Teresa Carrì, Tilmann Achsel, Mauro Cozzolino

Research output: Contribution to journalArticle

Abstract

A common feature of non-coding repeat expansion disorders is the accumulation of RNA repeats as RNA foci in the nucleus and/or cytoplasm of affected cells. These RNA foci can be toxic because they sequester RNA-binding proteins, thus affecting various steps of post-transcriptional gene regulation. However, the precise step that is affected by C9orf72 GGGGCC (G4C2) repeat expansion, the major genetic cause of amyotrophic lateral sclerosis (ALS), is still poorly defined. In this work, we set out to characterise these mechanisms by identifying proteins that bind to C9orf72 RNA. Sequestration of some of these factors into RNA foci was observed when a (G4C2)31 repeat was expressed in NSC34 and HeLa cells. Most notably, (G4C2)31 repeats widely affected the distribution of Pur-alpha and its binding partner fragile X mental retardation protein 1 (FMRP, also known as FMR1), which accumulate in intra-cytosolic granules that are positive for stress granules markers. Accordingly, translational repression is induced. Interestingly, this effect is associated with a marked accumulation of poly(A) mRNAs in cell nuclei. Thus, defective trafficking of mRNA, as a consequence of impaired nuclear mRNA export, might affect translation efficiency and contribute to the pathogenesis of C9orf72 ALS.

Original languageEnglish
Pages (from-to)1787-1799
Number of pages13
JournalJournal of Cell Science
Volume128
Issue number9
DOIs
Publication statusPublished - 2015

Keywords

  • Amyotrophic lateral sclerosis
  • C9orf72
  • mRNA
  • Stress granules

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

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    Rossi, S., Serrano, A., Gerbino, V., Giorgi, A., Di Francesco, L., Nencini, M., Bozzo, F., Schininà, M. E., Bagni, C., Cestra, G., Carrì, M. T., Achsel, T., & Cozzolino, M. (2015). Nuclear accumulation of mRNAs underlies G4C2-repeat-induced translational repression in a cellular model of C9orf72 ALS. Journal of Cell Science, 128(9), 1787-1799. https://doi.org/10.1242/jcs.165332